Tumor necrosis factor (TNF) is an important proinflammatory cytokine with pleiotropic biological effects, including the upregulation of numerous airway epithelial cell target proteins. In addition, TNF has been implicated as an important modulator of airway inflammatory events in disorders such as asthma. Airway epithelial cells express receptors for TNF and therefore represent target cells for TNF in the airway microenvironment. Therefore, it is important that airway epithelial cells participate in the regulation of TNF bioactivity so that excessive TNF-mediated proinflammatory effects can be attenuated. One mechanism via which TNF bioactivity can be regulated is the shedding of cell surface TNF receptors. This down-regulates the number of cell surface TNF receptors available for ligand binding and also generates a pool of soluble TNF receptors that may act as TNF binding proteins and inhibit TNF bioactivity. We have previously reported that protein kinase C activation by phorbol ester or IL-1_ can induce shedding of the 55 kDa type I TNF receptor (TNF-RI) from human airway epithelial cells. This is associated with a decrease in total cellular TNF-RI numbers. Conversely, corticosteroids inhibit TNF receptor shedding and increase total cellular TNF-RI numbers. However, the mechanism via which TNF receptor shedding occurs is unknown. Studies continue to be directed at identifying the proteolytic enzyme responsible for TNF-RI shedding and characterizing its function and expression.